An important challenge in developing treatments that induce weight loss and prevent weight regain is to identify regulatory mechanisms that can be targeted for drug therapy. Invertebrate models have commonly been used to discover new candidate genes for medicine. This proposal will use the honey bee for this purpose because the bee undergoes a striking, predictable and stable loss of abdominal fat as it grows up. Naturally occurring, stable weight loss occurs in few species, and not at all in major genetic model systems. The bee is well suited to this task because it not only undergoes stable weight loss but also is amenable to considerable manipulation. The goal of this project is to use a new animal model, state-of-the-art genomics and systems biology techniques, and a novel insect-mammal coupling to identify genes that are important in regulating weight loss. We will first test the hypothesis that age-related changes in gene regulatory networks (GRNs) in brain circuits and fat cells are associated with stable lipid loss. We will develop detailed profiles of gene expression for abdominal fat cells and for three populations of brain cells that are important for the regulation of lipid stores. We will utilize a probabilistic Hidden Markov Modeling approach to develop a quantitative model of gene regulatory networks (GRNs) in these cells in order to identify key regulatory genes whose expression is causally linked to lipid loss. We will then test the hypothesis that age-related changes in gene regulatory networks associated with stable lipid loss are endocrine-mediated. We will test this hypothesis with a systems approach that combines genome-wide ChIP-chip analysis, RNAi, microarray expression profiling, and modeling. Preliminary results from both microarray and ChiP-chip experiments support both hypotheses. Finally, these studies will be used to identify "switch" genes that will be tested by genetic manipulations in mouse or rat to determine whether these genes regulate adiposity in mammals. The principal significance of this research is that it will provide important new insights into the molecular basis of the regulation of adiposity. PUBLIC HEALTH RELEVANCE: A major goal in fighting the obesity crisis in the United States is to develop treatments that induce weight loss and prevent weight regain, but in order to achieve this goal it is necessary to have a deep understanding of the mechanisms that control body weight. Honey bees, unlike most other animals, are able to achieve stable loss of fat tissue as part of their normal adult maturation. The goal of this proposal is to use genomic and systems biology techniques to identify "switch" genes that enable stable weight loss in the bee, and to test that these genes regulate body weight and energy metabolism in mammals.